ABSTRACT
Thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine, exhibits both pro-inflammatory and pro-homeostatic properties depending on the context and tissues in which it is expressed. It remains unknown whether TSLP has a similar dual role in the airways, where TSLP is known to promote allergic inflammation. Here we show that TSLP receptor (TSLPR)-deficient mice (Tslpr-/-) and mice treated with anti-TSLP antibodies exhibited increased airway inflammation and morbidity rates after bleomycin-induced tissue damage. We found that signaling through TSLPR on non-hematopoietic cells was sufficient for TSLP's protective function. Consistent with this finding, we showed that TSLP reduces caspase-1 and caspase-3 activity levels in primary human bronchial epithelial cells treated with bleomycin via Bcl-xL up-regulation. These observations were recapitulated in vivo by observing that Tslpr-/- mice showed reduced Bcl-xL expression that paralleled increased lung caspase-1 and caspase-3 activity levels and IL-1ß concentrations in the bronchial-alveolar lavage fluid. Our studies reveal a novel contribution for TSLP in preventing damage-induced airway inflammation.
Subject(s)
Apoptosis/drug effects , Caspase 1/metabolism , Cytokines/pharmacology , Protective Agents/pharmacology , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Animals , Apoptosis/genetics , Biomarkers , Bleomycin/adverse effects , Caspase 3/metabolism , Disease Models, Animal , Disease Susceptibility , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Humans , Immunoglobulins/metabolism , Immunohistochemistry , Inflammation/drug therapy , Inflammation/etiology , Inflammation/metabolism , Mice , Mice, Knockout , Protein Binding , Receptors, Cytokine/metabolism , Respiratory Mucosa/pathology , Respiratory Tract Diseases/drug therapy , Respiratory Tract Diseases/etiology , Respiratory Tract Diseases/metabolism , Signal Transduction/drug effects , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , bcl-X Protein/genetics , bcl-X Protein/metabolism , Thymic Stromal LymphopoietinABSTRACT
Basophils are evolutionarily conserved in vertebrates, despite their small numbers and short life span, suggesting that they have beneficial roles in maintaining health. However, these roles are not fully defined. Here we demonstrate that basophil-deficient mice exhibit reduced bacterial clearance and increased morbidity and mortality in the cecal ligation and puncture (CLP) model of sepsis. Among the several proinflammatory mediators that we measured, tumor necrosis factor (TNF) was the only cytokine that was significantly reduced in basophil-deficient mice after CLP. In accordance with that observation, we found that mice with genetic ablation of Tnf in basophils exhibited reduced systemic concentrations of TNF during endotoxemia. Moreover, after CLP, mice whose basophils could not produce TNF, exhibited reduced neutrophil and macrophage TNF production and effector functions, reduced bacterial clearance, and increased mortality. Taken together, our results show that basophils can enhance the innate immune response to bacterial infection and help prevent sepsis.
